Pharmacogenomics | CYP450 | Geeky Medics

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Introduction

Pharmacogenomics is the study of how an individual’s genetic makeup affects how they respond to certain medications.¹

Most people carry at least one genomic variant which affects how they will process commonly used medications.²

With subtherapeutic response in up to 50% of all prescriptions, and approximately one in every 20 hospital admissions directly due to drug adverse effects, pre-emptive screening to detect variation in established drug-gene pairs offers the opportunity to guide towards more effective prescribing.³

Personalised medicine

The expectation is that in the future, this will be routine practice so that the most appropriate prescription can be selected from the beginning, so called personalised medicine.⁴

Pharmacogenomic-guided drug and dose selection brings the additional benefits of reducing adverse effects, reducing the economic burden of excessive medication waste, and identifying those patients who may require closer monitoring post-prescribing.^{3, 5}

At present, drug-gene pairing predominantly analyses how genetic variance affects the function of CYP450 enzymes.

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CYP450s

Cytochrome P450s (CYP450s) are a group of enzymes found in most organisms, whose primary function is to process exogenous compounds, chemically altering them into more water-soluble compounds which can be more easily eliminated.^{3, 6}

The greatest concentration of CYP450s is present in the human gut and liver.^{3, 6}

The human genome encodes over 50 CYP genes, of which 12 are involved in the metabolism of up to 80% of commonly prescribed medications.³

P450 families

CYP450s are divided into subfamilies according to how much DNA sequencing they share.³

As with all proteins, changes in the DNA that encode the amino acid sequence that makes up the protein result in a different 3D structure and potential function.

CYP450 enzymes have specifically shaped access channels and active sites that determine the types of substrates they can process.⁶ DNA variation changes the shape of these channels and active sites.⁶

Extensive diversity in P450 gene sequences across populations, with corresponding variation in 3D structure and enzyme function, leads to significant inter-individual variation in response to medications.

P450 individual variation

An allele is one of two or more versions of a DNA sequence at a specific genomic location.⁷

An individual inherits two alleles, one from each parent. The variation in allele combinations determines the CYP450 genetic information we all carry – our CYP450 genotype.⁷

Over time, studies have learned to predict how genetic variation affects the 3D structure of the enzyme, and thus how those differences affect the overall function of that P450 enzyme.⁵

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Activity scores

To help order this allelic variation, a scoring system has been developed that categorises genotypes/phenotypes based on the most up-to-date information available.⁵

Categories stratify patients by expected enzyme function or activity scores. These categories allow the prediction of a likely response to certain medications known to be metabolised by specific enzymes, known as drug-gene pairs.^{6, 8}

Table 1. The range of possible activity scores across different CYP2D6 genotypes⁸

Phenotype	Activity score ranges of genotypes
CYP2D6 ultrarapid metaboliser	>2.25
CYP2D6 normal metaboliser	1.25–2.25
CYP2D6 intermediate metaboliser	0.25–1.25
CYP2D6 poor metaboliser	0

Metaboliser status

Normal metabolisers

For most enzymes, activity scores of one or more are considered normal, such that inheriting at least one fully functional allele, even alongside a poorly functional allele, still delivers normal function.⁶

Individuals found to have normal metaboliser status are expected to effectively clear medications predominantly metabolised by this enzyme, so we can generally dose these medications as normal.⁵

Poor metabolisers

Individuals inheriting two poorly functional alleles have no rescue from another fully or partially functional allele, so are categorised as having an enzyme activity score of zero.⁶

These individuals are very likely to experience adverse effects and sometimes toxicity if given medications reliant on clearance by this non-functional enzyme.

An alternative prescription is usually needed.⁵

Ultrarapid and rapid metabolisers

Individuals can express additional gene copies (clones) which code for highly functional enzymes, leading to rapid or ultrarapid metabolisers.^{3, 6}

This can also be a problem, as it can lead to therapeutic failure, with apparent underdosing at seemingly standard doses of medication due to unexpectedly rapid clearance of the drug from the body.

Intermediate metabolisers

This category contains patients with some, but not full, enzyme function. Representing a wide range of patients with enzymes exhibiting various degrees of reduced function, from 10% to 80%, all are currently classified in the same intermediate metaboliser category.⁶

If Drug X is prescribed at the same dose to two patients with enzyme functions as varied as those above, they are likely to have markedly different responses to the same dose of medication. Therefore, even with some pharmacogenomic knowledge available, it remains clinically difficult to prescribe with confidence and precision for this heterogeneous group.⁵

Precision dosing recommendations are becoming available for certain drug-gene pairs, and it is hoped that individualised accuracy will continue to improve for a greater number of drug-gene pairs in the future.⁹

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Clinical relevance

A growing evidence base is developing to add clinical relevance to pharmacogenomic theory, demonstrating that genotyping can help to effectively guide real-world prescribing.⁵

Fluoropyrimidines

Fluoropyrimidine medications (e.g. 5-fluorouracil, capecitabine) are routinely used in a variety of cancers, including gastrointestinal and breast cancers.^9-10

It became apparent that up to 10% of patients receiving fluoropyrimidine chemotherapy were more susceptible to excessive, sometimes life-threatening toxicity, from otherwise standard doses.^9-10

Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme responsible for clearing these compounds.^9-10

Pharmacogenomic testing for allele variants highlighted why certain patients were having unexpected toxicity. Four alleles were identified to be associated with severe fluoropyrimidine-related toxicity, and these variants, leading to partial or absolute loss of DPD enzyme activity, are present in about 5% of patients.¹⁰

Clopidogrel

Clopidogrel is an antiplatelet medication used to prevent repeat thrombotic episodes (secondary prevention) post-ischaemic stroke, myocardial infarction and in peripheral arterial disease.^15-16

Clopidogrel is inactive when first ingested and is a prodrug that requires metabolic conversion by CYP2C19 to its active antiplatelet form.^{15, 17}

CYP2C19 shows significant functional variation, with estimates suggesting that over 25% of the population may have poor or intermediate CYP2C19 function.^17-18

The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend selecting an alternative antiplatelet for those with poor or intermediate CYP2C19 status because of the risk of therapeutic failure.¹⁷

Point of care testing for CYP2C19 status is currently being piloted at four hyper-acute stroke units across the UK, so that post-ischaemic stroke, those patients least likely to respond to clopidogrel can be identified and issued an alternative antiplatelet.^18-20

Codeine

Codeine is a synthetic opiate used as an analgesic and anti-tussive.²¹

It is not considered particularly active as an analgesic until it is converted in the body to morphine, with CYP2D6 mediating this conversion.^{3, 21}

CYP2D6 poor and intermediate metabolisers have been shown to have subtherapeutic analgesic responses to codeine, with up to 20% of patients being intermediate metabolisers.^{3, 21-22}

CYP2D6 ultrarapid metabolisers may convert far more than 10-15% of codeine into active morphine, and therefore, seemingly standard doses of codeine may result in an opiate overdose.^{21, 23}

Dihydrocodeine is not known to be affected by CYP2D6 metaboliser status to the same extent, and increased use of pharmacogenomic testing may lead to a shift in prescribing habits toward dihydrocodeine to address this issue.^24-25

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The future

Pharmacogenomics will continue to expand and become another tool for use in everyday clinical practice.⁴ Plans are in place to significantly increase capacity for genomic testing and for patients to essentially have their genomics passport at their disposal, allowing the NHS to get upstream of ill health and make a reality of precision medicine.⁴

In the final quarter of 2024/25, just over 200,000 genomic tests were performed, with the majority (59%) in cancer patients.²⁶ The aim is to push this into the millions of tests annually.⁴

National genomic test directory

The National Genomic Test Directory lists the genomic tests commissioned by the NHS in England, including eligibility criteria.²⁷

At present, it requests that tests be performed in line with NICE guidance, only if the result is highly likely to change the patient’s or their family’s clinical management.²⁷

As laboratory capacity increases and the evidence base expands, this directory continues to grow.

Patient demand

Recent research has shown an enormous appetite among patients for pharmacogenomic testing, with 89% of participants willing to undergo it, driven by the potential to improve medication efficacy and reduce adverse drug reactions.²⁸

Additionally, 91% sought access to the results, emphasising the importance of patient empowerment and greater involvement in healthcare decisions.²⁸

The PROGRESS trial was a feasibility study of the practicalities of embedding pharmacogenomic-led prescribing within primary care, with recruitment at 21 GP practices across the UK.²⁹

Impact on healthcare professionals

An enormous effort is required to upskill the future healthcare workforce in this area.

A recent survey of over 1000 pharmacists across the UK found that 78% did not feel prepared to use genomics in their day-to-day work.³⁰

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Potential concerns

Patient surveys have shown that there is a reasonably consistent proportion of patients who will remain sceptical about this advance in therapy – up to 10%.²⁸

Currently, in the UK, a moratorium has been granted to keep genetic data secure, out of the hands of those with commercial interests.³¹ Other jurisdictions are already having difficulty containing this, and medical ethics leads will need to continue guiding in this area.³²

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Conclusion

Adding pharmacogenomic information into consultations will prove helpful, though it adds significant complexity.

Once we understand how best to utilise this knowledge and protect data, we will have an additional tool at our disposal to improve patient care.

The onus is now on current and future clinicians to upskill in the use of pharmacogenomics to provide the most appropriate care for future patients.

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Editor

Dr Jamie Scriven

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References

1. National Genomics Education Programme. Introduction to pharmacogenomics. 2025. Available from: [LINK].  
2. National Human Genome Research Institute. Pharmacogenomics fact sheet. 2025. Available from: [LINK].
3. Taylor C, Crosby I, Yip V, et al. A review of the important role of CYP2D6 in pharmacogenomics. Genes. 2020. Available from: [LINK].
4. Department of Health and Social Care (UK). 10‑year health plan for England: fit for the future. 2025. Available from: [LINK].  
5. Clinical Pharmacogenetics Implementation Consortium (CPIC). CPIC guidelines. 2025. Available from: [LINK].
6. Coleman M. Human drug metabolism: An introduction. Chichester: Wiley. 2005.
7. National Genomics Education Programme. Genomics glossary. 2025. Available from: [LINK].
8. Duarte JD, Thomas CD, Lee CR, et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6, ADRB1, ADRB2, ADRA2C, GRK4, and GRK5 Genotypes and Beta-Blocker Therapy. Clinical Pharmacology and Therapeutics. 2024. Available from: [LINK].
9. National Genomics Education Programme. Dihydropyrimidine dehydrogenase (DPD) deficiency. 2025. Available from: [LINK].
10. Keen J, McDermott J, Aguilar‑Martinez E, et al. Pharmacogenomics: DPYD and prevention of toxicity. Clinical Oncology. 2025. Available from: [LINK].
11. Medicines and Healthcare products Regulatory Agency (MHRA). 5-fluorouracil (intravenous), capecitabine, tegafur: DPD testing recommended before initiation to identify patients at increased risk of severe and fatal toxicity. 2020. Available from: [LINK].
12. CPIC. CPIC® Guideline for Fluoropyrimidines and DPYD. 2024. Available from: [LINK].
13. UK Chemotherapy Board. Personalised Medicine Approach For Fluoropyrimidine-based Therapies. 2020. Available from: [LINK].
14. Knikman JE, Wilting TA, Lopez‑Yurda M, et al. Survival of Patients With Cancer With DPYD Variant Alleles and Dose-Individualized Fluoropyrimidine Therapy—A Matched-Pair Analysis. Journal of Clinical Oncology. 2023. Available from: [LINK].
15. Electronic Medicines Compendium (eMC). Plavix 75 mg film‑coated tablets. 2025. Available from: [LINK].
16. Intercollegiate Stroke Working Party. National Clinical Guideline for Stroke. 2023. Available from: [LINK].
17. Lee CR, Luzum JA, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update. 2022. Available from: [LINK].  
18. Matos A. Lessons from testing 2,300 patients at the UK’s first CYP2C19 genotyping system. The Pharmaceutical Journal. 2024. Available from: [LINK].
19. North West Genomic Medicine Service Alliance. Clopidogrel pilot project: CYP2C19 genetic testing in stroke and TIA patients. 2025. Available from: [LINK].
20. NICE. CYP2C19 genotype testing to guide clopidogrel use after ischaemic stroke or transient ischaemic attack. 2024. Available from: [LINK].
21. Hindmarsh J, Au YK, Pickard J. How codeine metabolism affects its clinical use. The Pharmaceutical Journal. 2021. Available from: [LINK].
22. CPIC. CPIC® Guideline for Opioids and CYP2D6, OPRM1, and COMT. 2020. Available from: [LINK].
23. Gasche Y, Daali Y, Fathi M, et al. Codeine Intoxication Associated with Ultrarapid CYP2D6 Metabolism. New England Journal of Medicine. 2004. Available from: [LINK].
24. Ammon S, Hofmann U, Griese EU, et al. Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing. British Journal of Clinical Pharmacology. 2001. Available from: [LINK].
25. Schmidt H, Vormfelde SV, Walchner‑Bonjean M, et al. The role of active metabolites in dihydrocodeine effects. International Journal of Clinical Pharmacology and Therapeutics. 2003. Available from: [LINK].
26. NHS England. Genomic testing activity. 2025. Available from: [LINK].
27. NHS England. National Genomic Test Directory. 2025. Available from: [LINK].
28. Magavern E, Marengo G, Participant Panel at Genomics England, et al. A United Kingdom nationally representative survey of public attitudes towards pharmacogenomics. QJM. 2025. Available from: [LINK].
29. North West Genomic Medicine Service Alliance. Spotlight: PROGRESS project. 2025. Available from: [LINK].
30. National Genomics Education Programme. Genomics in your practice: a pharmacy survey to help us support you. 2025. Available from: [LINK].
31. Association of British Insurers. Code on Genetic Testing and Insurance: Annual report. 2025. Available from: [LINK].
32. Fraser H, Gamet K, Jackson S, et al. Genetic discrimination by insurance companies in Aotearoa New Zealand: Experiences and views of health professionals.New Zealand Medical Journal. 2023. Available from: [LINK].

Image references

• Figure 1. Taylor C, Crosby I, Yip V, et al. Figure 4. A Review of the Important Role of CYP2D6 in Pharmacogenomics. Genes. Licence: [CC BY 4.0].

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